PROJECT SUMMARY Alzheimer's disease (AD) dementia is a progressive neurodegenerative disorder that is common among older individuals and typically associated with episodic memory loss. The pathophysiological processes of AD begin decades before the emergence of clinical symptoms of dementia, providing an opportunity to understand early disease mechanisms and the contribution of this pathology to memory decline in ?normal? aging. Along these lines, reductions in memory within the clinically normal range are observed across the lifespan, showing subtle but consistent decrements at each decade between the 20's and 80's. Interestingly, the two hallmark pathologies of AD, the accumulation of Tau into neurofibrillary tangles (NFTs) and beta-amyloid (A?) into plaques, show distinct time courses and regional involvement across the lifespan. Specifically, NFTs restricted to the entorhinal cortex are common in middle age and ubiquitous in older age (50% of 50 year olds and 90% of 70 years olds have NFTs in entorhinal cortex), whereas abnormal A? is uncommon in middle age but prevalent at older ages and tends to be distributed throughout cortex (10% of 60 year olds and 30% of 75 year olds). Exacerbation of NFTs in entorhinal cortex and into other portions of the medial temporal lobe (MTL) and neocortex is coupled with A? accumulation. Recent advances in human PET imaging now enable in vivo visualization of Tau accumulation, providing a critical opportunity to establish the impact of Tau accumulation and the synergistic interaction between Tau and A? on memory decline in aging. However, the ability to measure PET signal directly from the hippocampus using first generation Tau tracers, such as AV1451, have been compromised by off-target binding in the choroid plexus adjacent to the hippocampus. Recently evolving second-generation tracers that show less off-target binding to choroid plexus, such as [18]F-PI2620, may improve the ability to investigate Tau in the aging hippocampus. Moreover, advancements in MRI enable the collection of ultra high-resolution structural and high-resolution functional measures of MTL subregions (via 7T and 3T scanning). We therefore propose to incorporate a novel second-generation Tau tracer into an ongoing neuroimaging study of aging at Stanford with existing MRI and CSF data (PI: Anthony Wagner, R01AG048076) to enable the comparison of regional Tau in entorhinal cortex and the hippocampus to high-resolution measures of MTL integrity. Although CSF Tau is available, this measure does not provide a regionally precise measure of Tau accumulation in the MTL, highlighting the importance of adding Tau PET into a study focused on age-related changes in the MTL. Furthermore, the timeframe of this grant is ideal given that the R01 parent study is midway through enrollment, allowing Tau PET to be added during the second half of enrollment, resulting in minimal delay between existing CSF/MRI data and Tau PET (?6 months). Overall, this work will improve fundamental understanding of etiologies underlying age-related changes to the MTL, the impact of MTL Tau on hippocampal mechanisms of memory, and ultimately predictive risk of AD dementia.